Autoimmune disease

Question 1

Give 2 examples of organ-specific autoimmune disease

Answer 1

• Graves - TSH receptors in thyroid

- Type 1 diabetes - beta cells of pancreas

Question 2

Give examples of HLA B27-associated spondyloarthropathies

Answer 2

• Ankylosing spondylitis, undifferentiated spondyloarthropathu, reactive arthritis, psoriatic arthritis, urethritis, iritis
• Spectrum of severity and HLA B27 associated
• Associated with bowel inflamamtion

Question 3

What is autoimmunity?

Answer 3

• The immune system has various regulatory controls to prevent it from attacking self-proteins and cells.
• Failure of these controls will result in immune attack of host components – known as autoimmunity.

Question 4

What is immune tolerance?

Answer 4

• Immune system doesnt attack self proteins or cells - it is tolerant to them
• Central tolerance - destroy self-reactive T or B cells before the enter the circulation
• Peripheral tolerance - destroy or control any self-reactive T or B cells which dont enter the circulation

Question 5

How does central tolerance deal with B cells?

Answer 5

• If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

Question 6

How does the thymus choose which T cells to keep?

Answer 6

• Doesn’t bind to any self-MHC at all = death by neglect (apoptosis)
• Binds self-MHC too strongly = negative selection - apoptosis
• Binds self-MHC weakly = positive selection, signal to survive

Question 7

What is AIRE?

Answer 7

• Autoimmune regulator
• promotes self-tolerance by allowing thymic expression of genes from other tissues
• Mutations in AIRE result in multi-organ autoimmunity
• Allows all of the proteins to be presented in the thymus, to allow selection, but problem with it causes rampant autoimmunity
• Autoimmune polyendocrinopathy syndrome type 1 -> hyperPT, hyperT, adrenal failure etc

Question 8

What happens if autoreactive T cells survive central tolerance control?

Answer 8

Peripheral tolerance

• Ignorance
• Anergy
• Regulation

Question 9

What is ignorance?

Answer 9

• if antigen is present in too low a conc to reach the threshold for T cell receptor triggering (immunologically privileged site eg brain, eye)

Question 10

What is anergy?

Answer 10

• Naive T cells need costimulatory signals in order to become activated - MHC-T-cell interaction, co-stimulatory signal and cytokine signal
• Most cells lack costim proteins and MHC class II
• If a naive T cell sees its MHC/peptide ligand without appropriate costimulatory protein, it becomes anergic
• So if APC doesnt present B7 for CD28 receptor, it wont proliferate and so will become anergic

Question 11

What is regulation?

Answer 11

• Treg cells can inhibit other T cells
• can stop T cell response by using inhibitory signals (IL-10 and TGF-beta) on nearby T cells
• FOXP3 is a TF of Treg cells to help regulate T cells
• Defective Treg can cause autoimmunity
• CD4+ and CD25+

Question 12

What happens if there is a mutation in FOXP3?

Answer 12

• Can lead to severe and fatal autoimmune disorder - IPEX syndrome

Question 13

How are there different types of MHC?

Answer 13

• Each copy of chr6 carries 3 different MHC class I (a,b,c) and 3 different MHC class II genes (DR,DP,DQ)
• High levels of genetic variation (polymorphism)

Question 14

What gender differences are there in autoimmune disease?

Answer 14

• SLE and MS are 10 times more common in females
• Diabetes is equal
• Ankylosing spondylitis is 3x more common in males

Question 15

What environmental factors may affect it?

Answer 15

• Hygiene hypothesis

- Smoking and RA

Question 16

What might trigger a breakdown of self-tolerance?

Answer 16

• Loss of/ problem with reg cells
• Release of sequestered Ag
• Modification of self
• Molecular mimicry

Question 17

Modification of self - what is citrullination?

Answer 17

• Citrullin is an AA, not coded for by DNA
• Arginine can be converted to citrulline as post translational modification by PAD enzymes
• citrullination may be increased by inflammation
• Autoantibodies to citrullinated proteins are seen in RA
• Now used for diagnosis

Question 18

How does molecular mimicry cause rheumatic fever?

Answer 18

• Disease is triggered by infection of streptococcus pyogenes
• Abs to strep cell wall Ags may cross-react with cardiac muscle
• Plasma cell produces Abs, binds to bacteria and clears disease
• Same Ab cross-reacts with heart tissue -> rheumatic fever

Question 19

What causes graves?

Answer 19

• Autoantibodies bind to TSH receptor and stimulate it -> hyperT
• Disease can be transferred from mother to foetus with IgG Abs

Question 20

What causes Myasthenia gravis?

Answer 20

• Autoantibodies bind to Ach receptor and block Ach binding
• Also leads to receptor internalisation and degradation
• Causes muscle weakness, as no Na influx, so no muscle contraction

Question 21

What causes SLE?

Answer 21

• Autoantibodies to soluble antigens form immune complexes
• Deposited in tissue, e.g. blood vessels, joints, renal glomeruls
• Can lead to activation of complement and phagocytic cells
• Immune complexes depositing in kidney can lead to renal failure

Question 22

What happens if IgG mediated autoimmune antibodies cross the placenta?

Answer 22

• Patient with graves makes anti-TSHR Abs
• Transfer of Abs cross the placenta into the foetus
• Newborn infant also suffers from grave
• plasmaphoresis removes maternal anti-TSHR Abs and cure the disease

Question 23

How do T-cells cause autoimmune disease?

Answer 23

• Direct killing by CD8+ CTL
• Self-destruction induced by cytokines such as TNFa
• Recruitment and activation of macrophages lead to bystander tissue destruction
• MS
• Insulin-dependent DM

Question 24

What are Th17 cells?

Answer 24

• T helper cells that produce IL-17
• They are implicated in autoimmune diseases such as spondyloarthropathy, MS and diabetes
• Highly inflammatory
• Produce cytokines involved in recruitment, migration and activation of immune cells -> more and more damage

Question 25

What therapeutic strategies do we have against autoimmune diseases?

Answer 25

• NSAIDs and corticostroids to dampen down inflammation
• T and B cell depletion (anti-TNF, anti-VLA4 (blocks adhesion))
• Antigen specific therapies in development